Hexavalent chromium, Cr(VI), has been used in a wide-range of industries, such as chrome plating, welding, painting, and metal finishes, for more than a century. Cr(VI) deposited as waste in landfills and waterways by chromate industries is a significant potential environmental hazard. Despite conservation and recycling efforts in the United States, however, over 20,000 metric tons of Cr(VI) are released into the environment every year with over 5,000 metric tons released as atmospheric emissions. Consequently, millions of people, including a majority of industrial workers, are exposed to Cr(VI). By an anion transport mechanism Cr(VI) readily enters the cell and the health consequences are not fully understood. Female infertility has increased in industrialized countries. Women working in Cr industries experience abnormal menses and have high blood levels of Cr(VI) that can be transported from mother to offspring through milk. If lactating women working in a Cr industry or living in an area exposed to high Cr intake through food or drinking water breast-feed their offspring, there is a potential risk that Cr(VI) in the mother's milk will affect ovarian development of the offspring. Toxic effects resulting from lactational exposure to Cr(VI) on ovarian follicular development, puberty, and reproductive health of developing offspring remain an enigma, and the principal cellular and molecular mechanisms underlying chromium toxicity on ovarian development are not known. The primary goal of the proposed research is to unravel the mechanisms by which lactational exposure to Cr(VI) impairs ovarian development and induces follicular atresia. This aim will be met by testing the hypothesis that lactational exposure to Cr(VI) impairs ovarian follicular development and induces follicular atresia and apoptosis in the offspring. Our Specific Aims are to: (1) Determine the effects of lactational exposure to Cr(VI) on ovarian follicular development in the offspring, and (2) Determine the effects of lactational exposure to Cr(VI) on ovarian follicular atresia and apoptosis in the offspring. Lactating rats will be exposed to Cr(VI) through drinking water during the first three weeks of postpartum so that the prepubertal (suckling) rats will receive chromium through mother's milk. Effects of Cr(VI) toxicity on ovarian follicular development, follicular atresia and granulosa cell apoptosis will be studied in these offspring on postnatal days 25, 35 and 65. Effect of Cr(VI) on caspase-3 dependent apoptotic pathway will be determined. Completion of studies outlined in this project are expected to provide new knowledge and increased understanding of mechanisms responsible for Cr(VI)-induced toxicity on ovarian follicular development and follicular atresia. These findings from a rat model can then be translated to strategies for protection of the reproductive health of women and their female offspring, especially those exposed to Cr, and thus support the missions of NIH and NIEHS. PUBLIC HEALTH RELEVANCE: Hexavalent chromium, Cr(VI), is used in a wide-range of industries, and millions of people and a majority of industrial workers have been exposed to Cr(VI) wastes in the workplace, landfills and waterways and every day atmospheric emissions. Cr(VI) is known to cause lung cancers, disrupt embryo and fetal development and induce reproductive abnormalities in women. The focus of the present project is to determine the effects of lactational exposure to Cr(VI) on ovarian follicular development and degeneration (atresia and apoptosis) in the offspring during their different developmental ages, and thus completion of studies outlined in this project should provide new knowledge essential to understand the mechanism of Cr(VI) toxicity on ovarian follicular development and follicular atresia which can be translated to protect reproductive health of women, especially those working in industries in which they are exposed to Cr(VI).